Natural Products in the “Marketplace”: Interfacing Synthesis and Biology

Abstract

Drugs are discovered through the biological screening of collections of compounds, followed by optimization toward functional endpoints. The properties of screening collections are often balanced between diversity, physicochemical favorability, intrinsic complexity and synthetic tractability. 1 Whereas natural product (NP) collections excel in the first three attributes, NPs suffer a disadvantage on the last point. Academic total synthesis research has worked to solve this problem by devising syntheses of NP leads, diversifying late-stage intermediates or derivatizing the NP target. This work has led to the discovery of reaction mechanisms, the invention of new methods and the development of FDA-approved drugs. Few drugs, however, are themselves NPs; instead NP-analogs predominate. Here we highlight past examples of NP analog development and successful NP-derived drugs. More recently, chemists have explored how NP analogs alter the retrosynthetic analysis of complex scaffolds, merging structural design and synthetic design. This strategy maintains the intrinsic complexity of the NP but can alter the physicochemical properties of the scaffold, like core instability that renders the NP a poor chemotype. Focused libraries based on these syntheses may exclude the NP but maintain the molecular properties that distinguish NPspace from synthetic space, 2 properties that have statistical advantages in clinical progression. 3,4 Research that expedites synthetic access to NP-motifs can prevent homogeneity of chemical matter available for lead discovery. Easily accessed, focused libraries of NP scaffolds can fill empty but active gaps in screening sets and expand the molecular diversity of synthetic collections.

Dehydration reactions in polyfunctional natural products

“…[9][10][11][12] Although daunting selectivity challenges typically need to be overcome, the direct modification of natural products, peptides or drugs offers access to novel compounds for structure-activity analysis or synthetic utility by further derivatization. 7,12 Hydroxyl groups are ubiquitous in natural products and their selective functionalization have been subject to significant interest. Interestingly, despite of the development of methods involving reagent control as well as bespoke catalysts, 11,12 e.g.…”

Antiproliferative Activity of Mycalin A and Its Analogues on Human Skin Melanoma and Human Cervical Cancer Cells

“…In this paper we report that mycalin A (1) and some of its synthetic analogues (4-11) possess a strong antiproliferative activity on human melanoma (A375) and human cervical adenocarcinoma (HeLa) cells. A degraded C4 lactone derivative of mycalin A (11) has displayed a remarkable selective cytotoxicity towards tumor cells in comparison with healthy control cells.…”

Guided by evolution: from biology oriented synthesis to pseudo natural products

“…Advances in synthetic methodology and total synthesis have enabled access to complex scaffolds and the chemoselective derivatisation thereof for structure-activity relationship (SAR) studies. [3][4][5][6][7] In addition, through elegant distortions of the NPs core-scaffold, unprecedented structural motives can be accessed. This approach was termed "Complexity-to-Diversity" (CtD) and enabled the discovery of novel biologically active molecules from terpenes, 8,9 steroids 8 and alkaloids.…”